ProjectSummary/Abstract(30linespermitted) Hookworms (genera Ancylostoma and Necator) and Haemonchus contortus are related (clade V, suborder Strongylida) blood-feeding gastrointestinal nematode (GIN) parasites of humans and ruminants. In humans, hookwormsarealeadingcauseofanemiagloballyandoneofthemostmedicallyimportantparasitesonearth, infectinghalfabillionpeopleandcausinggrowthstunting,cognitiveimpairment,malnutrition,andlossoffuture earnings/education/productivity. In small ruminants (e.g., sheep, goats), Haemonchus is one of the most importantanddevastatingparasites,withinfectionsleadingtoseveredehydration,anemia,lethargy,depressed low-energybehavior,roughhaircoats,lowweights,andpoorwoolandlambproduction.Infectionscanbelethal. Drug efficacy is becoming limited for both groups of parasites, with resistance emerging in humans and widespread in sheep. Therefore, complementation of drug treatment with a prophylactic vaccine would be an enormous step forwardfor controlandeventualelimination ofblood-feeding GIN parasites. However, vaccine development against blood-feeding GINs is complicated because these parasites are masters at evading the immunesystem.Weproposetousestate-of-theartgenomic,transcriptomic,andimmunoinformatictechniques toidentifyandprioritizenovelvaccinetargetsagainstblood-feedingGINs.Preliminarydataareencouraging.We will use our promising preliminary data to investigate what constitutes a good vaccine against blood-feeding GINs,aswellastoimprovetheefficacyofonevaccinecandidatebyalteringexpressionplatformsandadjuvants. Furthermore,wewillusegenomics,transcriptomics,andimmunoinformaticstocompareintestinal-specificgenes encoding putative secreted proteins between these two blood-feeding parasites, and to compare immunomodulatedgenesencodingputativesecretedintestinalproteinsbetweenthesetwonematodeparasites. These comparisons will be used to identify conserved, high-value blood-feeding-specific GIN antigens. These candidateantigenswillbetestedfirstinoursmallanimalmodelofhumanhookworminfectiontoidentifysingle hookwormvaccineantigens,and/oracombinationofhookwormvaccineantigens,thatwillengendercomplete or near-completeprotection from infection in the laboratory. Promisingantigens will be rapidly transferredtoa large animal system;? sheep will be vaccinated with the corresponding H. contortus antigens and similarly assessed for protection. Immunological and mechanistic aspects of protection will be studied. Our goal is to identifyoneormoreimmunogensthatcanbeoptimizedinpre-clinicalstudiesandthenadvancedtohumanand ovine/caprineclinicaltrials.